The present invention provides novel [3-substituted-2-(substituted imino)-4-oxo-5-thiazolidinylidene]acetic acids, and novel pharmacological compositions and methods of use thereof. The novel acids of the present invention are leukotriene antagonists having activity useful for treating asthma, allergies, cardiovascular diseases, migraines, and inflammation.
U.S. Pat. No. 3,873,524 discloses compounds of formula XL wherein R.sup.20 and R.sup.21 are lower alkyl of from one to six carbons. The compounds XL are disclosed as intermediates for the preparation of compounds useful in pharmacology but do not teach either pharmacological or biological activity for the intermediates themselves. Additionally the only species disclosed are compounds of Formula XL wherein R.sup.20 and R.sup.21 are methyl. On the other hand the compounds of the present invention are compounds having Formula I wherein R.sub.1 and R.sub.2 are alkyl of from five carbons to at least seven carbons or more and moreover the compounds wherein R.sub.1 and R.sub.2 are alkyl of five, six, seven, and eight carbons which are closest to the disclosure of U.S. Pat. No. 3,873,524 are now found to have pharmacological activity which is unexpected and surprising.
R. M. Acheson and J. D. Wallis disclose compounds of Formula XLI wherein R.sup.22 and R.sup.23 are the same and are methyl or phenyl in "Addition Reactions of Heterocyclic Compounds. Part 74. Products from Dimethyl Acetylenedicarboxylate with Thiourea, Thioamide, and Guanidine,"J. C. S. Perkin I pp. 415-422 (1981). No utility is disclosed for the esters of Formula XLI by Acheson et al and present compounds of Formula I having pharmacological activity are not within the teachings to these esters.
Similarly, U. Vogeli and W. von Phillipson teach esters of the Formula XLII wherein p-Brph is p-bromophenyl, Bzl is benzyl, Ph is phenyl and Me is methyl in "49. Structures of Addition Products of Acetylenedicarboxylic Acid Esters with Various Dinucleophiles. An Application of C,H-Spin-Coupling Constants," Helvetica Chimica Acta, Vol. 61, Fasc 2 (1978)-Nr 49. Again the present compounds having utility in pharmacology are not taught by Vogeli et al as there is neither a teaching to dihalo or trihalo phenyl in the R.sub.1 or R.sub.2 position of the Formula I nor a teaching to a utility.
H. Nagase, "Studies on Fungicides. XXI. Reaction of Dimethyl Acetylenedicarboxylate with Thioureas," Chem. Pharm. Bull. 21(2), 270-278 and 1132-1135 (1973) discloses a compound within the Formula XLII noted above but limited to benzyl substituents on the nitrogens. Again the compounds of the present invention having utility in pharmacology are not taught. Melika, et al, "Derivatives of 4-Thiazolinone and 4-Thiazolidinone based on some Acetylenecarboxylic acids," Uhr. Khim. Zh. 32(9), 1006-1008 (1966) of C.A. 66: 28704u (1967) also disclose an ester similar to the Formula XLII and further limited to a phenyl group on the imino nitrogen and an .alpha.-naphthyl on the remaining nitrogen.
Nagarajan et al "Addition Products of Dimethyl Acetylenedicarboxylate to Thiourea Studies on 2-(p-bromophenyl)imino-3-methyl-5-carbomethoxymethylenethiazolidin-4-one" of C.A 100: 209430z (1964) discloses a compound of Formula XLIII not included in the present invention and not teaching the compound of Formula I now having been found to be useful pharmacological agents.